Rapid assessment of the relative effectiveness of non-invasive prenatal testing for fetal aneuploidies

Noninvasive prenatal tests are in vitro diagnostic tests that use cell-free DNA (cfDNA) from the maternal blood of pregnant women for the identification of common chromosomal anomalies of the fetus, including T21, T18 and T13. The landscape of NIPT is diverse: some tests adopt polymerase chain reaction (PCR) for amplification of the cell-free DNA (cfDNA) before next-generation sequencing (NGS), while others rely on other methods of quantification such as chromosomal microarray analysis. Currently, NIPT is delivered mainly through private providers, not yet being available in publicly funded antenatal services outside the context of research studies in most European countries.

The objective of this EUnetHTA assessment was to evaluate the relative effectiveness and safety of noninvasive prenatal testing (NIPT) for the screening of fetal trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) in pregnant women of at least 8–9 weeks’ pregnancy.

Five screening pathways are considered for the purpose of NIPT assessment:

1. NIPT as a primary screening test (total replacement of the first trimester combined testing (FCT))

2. NIPT as part of FCT (replacement of serum testing)

3. NIPT as an add-on to FCT for the high-risk population

4. NIPT as an add-on to FCT for the high- and intermediate-risk population

5. NIPT as a replacement for invasive testing.

The effectiveness of the screening processes is evaluated in terms of secondary outcomes (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)), as well as in terms of primary outcomes, reducing unnecessary invasive tests. It is also based on assessing the impact on children born with undiagnosed T13, T18 and T21, natural miscarriages or stillbirths, and miscarriages related to invasive testing (amniocentesis or chorionic villus sampling (CVS)). False positive (FP) rates, false negative (FN) rates and test failures were chosen as critical safety issues. Randomised controlled clinical trials, nonrandomized controlled clinical trials and diagnostic test accuracy (DTA) studies on the index test, the comparator and the reference standard (cross-sectional studies) are included for the effectiveness and safety domain.

A systematic search of the scientific literature was performed in February to March 2017 in MEDLINE (PubMed), Embase (OVID SP), the Centre for Reviews and Dissemination (CRD) database, Web of Science and the Cochrane Library (Wiley). Ongoing clinical trials and research projects were found through ClinicalTrials.gov, the EU Clinical Trials Register, the International Clinical Trials Registry Platform (ICTRP) and the UK Clinical Trials Gateway.

Each study on general and high-risk pregnant population (15+ studies for each fetal trisomy)  considered had more than 20,000 pregnant women included, while “high- or intermediate-risk pregnant population” criteria had only one study for all fetal trisomies with 3633 pregnant women. Twin pregnancy population had six studies with 1985 pregnant women total, and only T21 was tested in this population.

Conclusion

• Existing moderate quality evidence supports that the detection of T21 cases is higher when NIPT replaces FCT as a primary screening test and that this replacement would lead to a reduction in unnecessary invasive testing. However, essential uncertainties remain regarding the under-reporting of missed cases given the inappropriate verification of negative results
• No data exist to assess the accuracy of NIPT offered as part of the first-trimester fetal combined test.
• The available data suggest that the use of NIPT as an add-on to combined testing for high-risk T21 population screening could also lead to substantial reductions in unnecessary invasive testing, although this needs to be confirmed with real-world data. The performance of the test (test failures, uncertain results) and the uptake of NIPT screening are among the factors that could contribute to change this ratio in real practice.
• There is lack of data to assess the use of NIPT as an add-on to combined testing for high- and intermediate-risk T21 populations.
• The low QoE for T18 and T13 does not allow conclusions to be drawn on these trisomies for any of the screening pathways.
• There is insufficient evidence to establish the accuracy of NIPT for twin pregnancies.
• Appropriately designed studies are required to be able to assess the performance of the different test strategies, taking into account detection of all anomalies, abortions, miscarriages and other patient-related outcomes. Substantial uncertainties remain regarding the best screening pathway.

See the full report in English here.

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